The purpose of this funding opportunity is to provide centralized
support and coordination for the studies and investigators funded under the
Population Architecture Using Genomics and Epidemiology (PAGE) program (RFA-HG-12-010),
who will sample and assess genomic variation from well-phenotyped individuals
of non-European (EA) ancestry and disseminate the resulting data to form a
population resource that will expand understanding of ancestral differences
in genomic disease associations. This four-year program will extend the
initial experience of PAGE I to add large-scale, dense assays of common and
rare coding and/or potentially functional genomic variation in a large number
of non-EA ancestry participants with existing and extensive phenotype
information.

Key Dates

Posted Date

June 20, 2012

Open Date (Earliest Submission Date)

September 18, 2012

Letter of Intent Due Date

September 18, 2012

Application Due Date(s)

October 18, 2012, by 5:00 PM local time of applicant
organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

February/March, 2013

Advisory Council Review

May, 2013

Earliest Start Date(s)

June, 2013

Expiration Date

October 19, 2012

Due Dates for E.O. 12372

Not Applicable.

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and
Contracts). Conformance to all requirements (both in the
Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

The purpose of this funding opportunity is to provide
centralized support and coordination for the studies and investigators funded
under the Population Architecture Using Genomics and Epidemiology (PAGE)
program (RFA-HG-12-010),
who will sample and assess genomic variation from well-phenotyped individuals
of diverse ancestry, particularly those of non-European ancestry (EA), and
disseminate the resulting data to expand understanding of ancestral differences
in SNP-disease associations observed in PAGE Phase I and similar studies. This
four-year program will extend the initial experience of PAGE I to add
large-scale, dense assays of common and rare coding and/or potentially
functional genomic variation in a large number of diverse ancestry
participants, particularly groups with disproportionate disease burdens, and
with existing and extensive phenotype information. For the purposes of this
FOA, “assess genomic variation” means using the most comprehensive and
cost-effective technology to capture the majority of inter-individual
variation; currently the “exome chip” but likely to evolve over the four-year course
of this FOA. Collections of “well-phenotyped individuals” may be
cross-sectional, if extensive, or, preferably, prospective and
longitudinal. “Non-EA” and “ancestrally diverse” populations refer to
individuals whose ancestral (e.g., grandparents’) continent of origin lies
outside Europe. “Potentially functional variation” means coding or non-coding
variants that influence genomic function and are related, or suspected of being
related, to human diseases.

The goals of this program are to collaboratively utilize
existing population-based cohorts to: 1) identify disease-associated genomic
regions where between-population differences may be attributable to differences
in allele frequency or LD structure; 2) build a population resource of non-EA
individuals whose comprehensive genotype and phenotype data would serve as a
reference population for the scientific community; and 3) explore the
associations of DNA sequence variation with a broad range of phenotypes,
including conditions with disproportionate disease burdens in persons of non-EA
ancestry.

This funding opportunity will provide support for activities
that will support the PAGE II Consortium and its Working Groups. The PAGE II
CC will have primary responsibility for organizing and coordinating cross-study
activities, as described further below.

To ensure that the maximal scientific benefit is derived
from this significant public investment, this funding opportunity aims to
support widespread sharing of the resulting data with the broad scientific
community for research use, through community resource databases such as dbGaP
(http://www.ncbi.nlm.nih.gov/gap)
or other databases to be developed within or outside this project.

Background

PAGE Phase I is an ongoing, five-year cooperative agreement
funded to utilize existing population-based cohort studies and clinical trials
to: 1) determine the population-based profile, or “epidemiologic architecture,”
of potentially causal variants, including prevalence in racial and ethnic
subgroups of relevance to the U.S. population and magnitude of disease risk and
associations with other health characteristics; 2) identify modifiers of
gene-trait associations, particularly lifestyle factors or medication use; and
3) identify potential clues to the biological basis of an association by
studying the relationship of the robustly associated variants to phenotypic
characteristics such as laboratory measures or imaging findings. In July,
2008, NHGRI funded 4 grants in response to RFA-HG-07-014, “Epidemiologic
Investigation of Putative Causal Genetic Variants” (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-07-014.html)
and 1 grant in response to RFA-HG-07-015, “Epidemiologic Investigation of
Putative Causal Genetic Variants – Coordinating Center”. Collectively, PAGE
analyses have included more than 100,000 participants, representing individuals
of European ancestry as well as individuals of African American,
Hispanic/Latino, Asian, Native Hawaiian, and American Indian ancestry. Among
the approximately 70,000 non-EA PAGE participants analyzed during the later
project years, 49% are African American, 31% Hispanic/Latino, 18% Asian, and 2%
Native Hawaiian. PAGE I analyses leveraged the considerable breadth and depth
of phenotypes from these cohorts to compare cross-population allele
frequencies, relative risks, and distribution of phenotypes associated with
particular variants and their environmental modifiers among populations of
European and non-EA descent. This work was accomplished through the formation
of many Working Groups, convened to harmonize phenotypes, conduct
consortium-wide meta-analyses and write manuscripts, and provide consistent
guidance across the consortium with regards to statistical analyses,
ethnicity/ancestry analysis, publications, and implications for data display
and dissemination. Key findings from PAGE I include characterization across
multiple ancestral groups of lipid and metabolic traits, stroke, coronary heart
disease, endometrial cancer, and type 2 diabetes. In addition to conducting
carefully harmonized and a priori analyses of specific traits, PAGE I analyzed
and deposited association data across nearly all phenotypes, yielding data
suitable for preliminary, highly exploratory phenome-wide association studies
(PheWAS).

As the limitations of characterizing a genome-wide
association study (GWAS) locus in diverse ancestry populations using a single
variant became evident, PAGE undertook a pilot study in 2009 to test the
feasibility and value of expanding genotyping to denser fine mapping around
many GWAS loci. This pilot study, made possible by the American Recovery and
Reinvestment Act (ARRA), genotyped approximately 5,000 African Americans using
the Metabochip, a dense genotyping array of ~200K SNPs, including
ancestry-specific fine mapping variants, for a range of metabolic and
cardiovascular traits. The resulting pilot data demonstrated a number of GWAS
associations that do not generalize to African American populations,
demonstrating the importance of dissecting GWAS signals in an ethnic-specific
way. Taking advantage of increased cost-efficiencies in genotyping arrays and
the need for dense genotyping data from diverse ancestry groups, in the latter
years of the project period PAGE is generating and analyzing Metabochip data on
approximately 70,000 participants of African American, Hispanic/Latino, Asian,
and Native Hawaiian descent. Summaries of the PAGE Steering Committee (SC) and
External Scientific Panel (ESP) discussions which led to this shift in
genotyping are available at https://pagestudy.org/index.php/public-documents.

PAGE II seeks to expand understanding gained during PAGE I
and similar studies of how ancestry-specific differences in allele frequencies
and LD may explain differences in risks of common traits and conditions. Recent
studies have identified rare genetic variants that are likely to contribute to
common diseases and traits and observed that rare variants likely to be
functional, such as those in coding and regulatory regions, tend to be
population-specific. PAGE II is expected to start with the most comprehensive
and cost-effective technologies currently available, such as the next
generation of high density genotyping arrays (e.g., exome chip) to continue its
emphasis on characterizing population-level disease risks in non-EA
individuals. As sequencing technologies advance in efficiency and decline in
cost, PAGE II may adopt more advanced approaches as was done in PAGE I.

Scientific
Knowledge to be Achieved

This funding opportunity and the related RFA-HG-12-010,
“Population Architecture Using Genomics and Epidemiology (PAGE), Phase II – Study
Investigators”, will provide detailed, population-based information on genomic
variants robustly associated with or strongly suspected of influencing complex
diseases and traits. It will do so in a rapid and cost-effective manner
by assaying these variants in representative population samples already
well-characterized for a number of phenotypic traits and exposure variables.
The individual-level genotype and phenotype data and resulting descriptive data
will be provided to an NIH-designated data repository for dissemination to the
scientific community.

Objectives
of this Research Program

This FOA will provide centralized support and coordination
for the studies and investigators funded under the Population Architecture
Using Genomics and Epidemiology (PAGE) program (RFA-HG-12-010),
who will sample and assess genomic variation from well-phenotyped individuals
of diverse ancestry, particularly those of non-European ancestry (EA), to
expand understanding of ancestral differences in SNP-disease associations
observed in PAGE Phase I. Applicants should describe their plans for coordinating,
facilitating and supporting the activities of this program in collaboration
with the Study Investigators and NHGRI. These activities will likely include,
but are not limited to:

Synthesizing individual-level genotype and phenotype data from
PAGE II Study Investigators to create one or more centralized datasets for
analytic use, including data cleaning and quality control (QC); and

Providing logistical and administrative support for the
consortium as a whole

Investigative groups will be responsible for study design,
genetic assays, analysis and data submission of their individual studies to the
CC and to dbGaP. The CC will be responsible for providing support and
assistance to accomplish the goals of the program. Applicants should describe
their experience in working as part of a research consortium or other
collaborative activities that included both laboratory and clinical/epidemiologic
partners. Together with the Study Investigator groups, the CC will work to
coordinate genotyping and analysis of disease-associated genomic regions where
between-population differences may be attributable to differences in allele
frequency and/or LD structure. To maximize the numbers of diverse and
well-phenotyped participants in PAGE II (at least ~10,000 participants per site
over the project period), cost-effective high-density SNP arrays will be the
primary source of genotyping technology. Whereas PAGE I focused on
characterizing findings from GWAS, PAGE II will focus on extending regions of
interest to findings from sequencing studies, particularly those in exonic or
potentially functional regions of the genome. Depending on the prevailing content
of exonic-focused genotyping arrays at the time PAGE II genotyping is underway,
efforts to augment this content with genetic variation representative of
diverse ancestry populations using additional genomic assays may be a key focus
of PAGE II. The final choice of genotyping array(s) or technology will be
discussed and agreed upon by the PAGE SC in conjunction with the NHGRI, and may
evolve over the project period. As in PAGE I, genotyping will likely revolve
around approximately yearly batches to facilitate cross-study analyses
throughout the project period. Investigators should describe the expertise that
makes them well qualified to address the challenges and opportunities inherent
to assessing and implementing rapidly changing technology to accomplish the
goals of PAGE II. These discussions will provide valuable guidance to the
studies participating in this program and to population studies in
general.

Once approaches for genetic investigations are generally
agreed upon, subsequent investigation within the consortium supported by this
program might include: 1) prioritizing appropriate participants within studies
to be assayed and the relevant phenotypic and exposure data to be used in
analyses; 2) conducting genotypic and other evolving genomic assays as needed
to characterize novel and reported associations; 3) contributing scientific
expertise to PAGE-wide phenotype harmonization efforts; 4) contributing
individual-level genotype and phenotype data to one or more PAGE-wide datasets
for centralized (i.e., consortium-wide) analyses; 5) analyzing the resulting
data in detail, in relation to all or nearly all the relevant phenotypic,
covariate/exposure, and population ancestry data available; and 6) inviting
collaborations with outside investigators for further functional or
translational research. The most rapid possible timeframe for these steps
should be proposed, and should continue to accelerate over the course of the
program as efficiencies and best practices evolve. The CC is expected to
be most actively involved in steps 3-6 above, particularly in developing
program-wide approaches to data synthesis and presentation that facilitate
collaboration and comparability across participating studies, as well as
promoting accessibility and ease of use for investigators outside the program.
The CC may also assist individual investigative groups as needed, and will work
with all participating groups to develop the framework for all the steps above.

Applications in response to this FOA should propose approaches
to consortium-wide phenotype harmonization efforts and data synthesis and
presentation that maximize information on population impact and potential gene
function, while minimizing spurious findings and difficulty sifting through the
resulting analyses. Innovative bioinformatic approaches for identifying and
displaying potentially important findings should be proposed and applied
program-wide, as appropriate, to increase the ease of use of the
consortium-wide results. Sharing of expertise and experience in this and other
areas across investigative groups, facilitated and encouraged by the CC and
NHGRI, will be a major goal of this collaborative program.

Applications should also propose methods for coordination
among investigative groups, analysis within and across participating studies
(to be conducted by the investigative groups and/or the CC as appropriate),
synthesis of findings, cataloguing the characteristics of participating
studies, and invitations to collaborate with participating studies. Applicants
should propose information to be collected from investigative groups to
describe their studies, such as source population, eligibility criteria,
informed consent and consultation process, breadth and quality of phenotype
data, and numbers and demographics of participants currently in the population
study or proposed for inclusion, as well as specific provisions of current
informed consent and IRB approvals for dissemination of individual-level
genotype and phenotype data and any restrictions on research use of the data.

Applications should describe how this information will be
collected from investigative groups, compiled and formatted, and, as needed,
provided to databases such as dbGaP, as well as approaches for reaching
consensus on program-wide approaches to providing these data. Although rigid
uniformity across all participating studies may be neither feasible nor
desirable, common approaches should be pursued to the degree possible to
promote efficiency, ease of use, and comparisons across studies.

Investigative groups funded through RFA-HG-12-010 will in general be expected to have the experience and expertise to
characterize their studies, and to perform and provide individual-level data in
an agreed-upon format. The CC is expected to organize the development of
standardized analysis plans and/or data submission templates, as decided upon
by the PAGE SC. In some instances, however, investigative groups may need
guidance and assistance from the CC in performing these functions. The CC
should be prepared to assist as needed, providing appropriate expertise both
for performing analyses and for developing the necessary analytic capabilities
within the investigative groups. The CC will also propose and implement
approaches for evaluating quality of the data provided by the investigative
groups for submission to dbGaP and similar databases. Although it is expected
that databases such as dbGaP will be the primary vehicle for disseminating
information about and from these studies to the scientific community, other
approaches may be appropriate and desired. Development of new tools and
databases for providing such information will be supported under this FOA; these
tools should be made freely available to the scientific community during the
course of this award and provisions proposed for turning their maintenance over
to a suitable archive at the end of the grant period.

The CC will also organize and facilitate discussions to
arrive at consensus genotyping array(s) or technology and relevant quality
control metrics within the consortium. Applicants should describe prior
experience with leading or participating in similar activities and proposed
approaches to collecting and disseminating this information. Each Study
Investigator applicant to RFA-HG-12-010 will include genotyping costs for his/her proposed research. Given the
importance of minimizing costs and maximizing efficiency, shortly after review
NHGRI will compare prevailing costs and timeframes for genotyping proposed at
each investigative site to centralized genotyping at large-scale, high
throughput facilities. Should NHGRI decide to centralize genotyping, the CC
awardee, under guidance from NHGRI, will solicit a subcontractor to perform
PAGE-wide genotyping. Additional funds would be provided for these genotyping
activities. Coordinating Center applicants should describe their approach for
selecting a centralized genotyping facility to ensure minimal costs and maximal
efficiency throughout the course of the project, but should not propose a
genotyping facility nor include genotyping costs in the budget at the time of
application. Upon request by NHGRI and following peer review, CC applicants
should be prepared to propose a budget for genotyping 40,000 samples from
investigative groups over the four-year project period, including personnel,
supplies, indirect costs, etc. Applicants should also describe prior
experience in collaborating with such facilities.

Pooling of analyses and harmonization of phenotypes across
investigative groups are expected to be major components of this program. A
key aim of PAGE II will be to take advantage of the large, ancestrally diverse
population samples collectively available throughout the consortium.
Accordingly, SI applicants will propose a set of cross-study analyses that
their group would be well suited to lead within PAGE II, recognizing that
cross-study analyses, prioritized by the SC, will be done where possible. The
PAGE II CC’s role in this process will be to organize phenotype harmonization
efforts; synthesize individual-level genotype and phenotype data from each
investigative group into one or more PAGE-wide datasets for analytic use, to
include data cleaning and QC; and disseminate this centralized dataset to PAGE
Investigators and to dbGaP or other data repositories. Sharing of expertise and
experience across investigative groups will be a major goal of this
collaborative program, with the intent of better understanding the
characteristics and implications of genetic variants that generalize across
multiple ancestry groups, and making the resulting findings available and
understandable to investigators from a wide range of disciplines.

The CC funded by this FOA will manage the logistics of the
program in collaboration with the NIH Program Office, including organizing
meetings and teleconferences, distributing materials, recording draft minutes
for Program Office review, etc. Costs for these activities and for three
in-person SC meetings per year, one of which will include travel for six ESP
members, should be included in the proposed budget. The CC will also be
responsible for obtaining reports and other information from the investigative
groups and preparing reports for review by NIH program staff, outside advisors
including the ESP, etc.

The CC will work collaboratively with investigative groups
and NCBI to provide information on study characteristics and descriptive data
for distribution through dbGaP. The exact boundaries of the activities of the
CC, the investigative groups, and NCBI are not possible to predict at this
time, and will depend in large degree on the capacities and experience of the
investigative groups. These responsibilities will need to be negotiated once
the project is funded and underway, and may change as scientific opportunities
present themselves. Applicants should describe their willingness to be flexible
in assuming or relinquishing responsibilities as program needs arise.

Funding will be provided to support methodologic development
and lead collaborative activities such as phenotype harmonization, technical
assessment or performance evaluation of various assays for genotyping or other
technology, and for analyzing, synthesizing, disseminating, and interpreting
the resulting data. No participant recruitment or direct data collection for
use in genome-wide studies (such as questionnaires, examinations, or laboratory
measures) will be supported by this FOA.

Program
Organization

The award funded under this FOA will be a cooperative
agreement (see Section VI.2.A. Cooperative
Agreement Terms and Conditions of Award). The solicitation: “RFA-HG-12-010,
Population Architecture Using Genomics and Epidemiology (PAGE), Phase II –
Study Investigators,” will support the investigative groups who will sample and
assess genomic variation from well-phenotyped individuals of non-EA ancestry to
expand understanding of ancestral differences in disease associations with
genomic variants. Close interaction among awardees and the NIH will be expected
to develop appropriate strategies and tools to carry out this program.
The awardees will meet as a Steering Committee (SC), which will include the PD(s)/PI(s)
from each investigative group, the Coordinating Center (CC), and the NIH
Project Scientist, to first examine the phenotypic, covariate, and exposure
data available in each participating population study, including the variables
collected, methods used, and documentation available. Sample sizes
specific for phenotypes of high program-wide priority and for major ancestral
groups will be assessed and documented by each awardee across all participating
studies. Information on study design, characteristics, and available data
will be compiled by each investigative group and provided to the CC for public
dissemination in a user-friendly manner. Information on study design,
characteristics, available data and quality and quantity of DNA available for
PAGE analyses will also be compiled by each investigative group and formatted
for public dissemination in a user-friendly manner.

Options for genomic investigations will be discussed by the
SC. Once a consensus regarding genotyping platform(s) is reached, the SC will
prioritize the highest priority genomic regions and their associated
phenotypes, in the context of the overall racial/ethnic distribution, for
characterization in the various ancestral groups. Although the primary
focus of PAGE II will be to further characterize disease-associated regions,
opportunities to use the data to facilitate discovery of novel genomic variants
across the allelic frequency spectrum will also be explored. The SC will also
identify strengths and weaknesses of the various participating studies in terms
of traits and covariates available for investigation, and suggest best uses for
specific studies, such as examining the impact of a particular risk factor on a
given genotype-phenotype association, or the risk of a specific trait
associated with a given variant. An important product of PAGE II will be
a collective dataset comprehensive of genotype and phenotype information, for
use by the scientific community as a reference for population-based estimates
of allele frequencies and association sizes across a broad range of phenotypes.
The CC will lead the formatting, harmonizing, and disseminating of PAGE II data
in one or more centralized datasets, including data cleaning and QC, and
actively engage the Study Investigators in this process.

Approaches to genotyping quality control, phenotype
harmonization, statistical analysis and data synthesis will be shared and
reviewed in SC meetings. The SC will propose and agree upon approaches to
establish an efficient cross-study analysis pipeline, with procedures and
results to be standardized as much as feasible across participating studies and
provided as rapidly as possible. These results will be compiled by the CC
and provided to the scientific community through databases such as dbGaP or
others to be developed through this program. Appropriate embargoes on
submission of publications from these findings, consistent with NHGRI and NIH
guidelines, will be applied. Investigative groups are required to share
genotype and phenotype data on individual study participants in databases such
as the controlled access portion of dbGaP, in keeping with NHGRI and NIH
policies.

The SC will meet in person three times per year and monthly
on conference calls as needed to share information on data resources,
methodologies, analytical tools, as well as data and preliminary results. PAGE
II will continue to have Working Groups in areas of interest to the awardees
and the funding institute(s). Currently PAGE I has several such groups focused
on phenotype harmonization and phenotype-specific analyses, along with
committees focused on ethnicity/ancestry, data display and dissemination,
statistical analysis, SNP selection and quality control, and implementation of
the Metabochip pilot and subsequent scale-up. The tasks of the Working Groups
will include, among other responsibilities: identifying common scientific areas
and adjusting projects to accommodate shared interests, identifying novel
projects that may result from synergy among the awarded groups, apprising the
SC on progress, and identifying ways to interact with external ongoing networks
and initiatives. Working Groups may propose new research collaborations
with non-network investigators and organizations, as long as most or all PAGE
sites have the opportunity to participate, according to criteria established by
the PAGE SC. Key co-investigators and pre- and postdoctoral trainees, in
addition to the PD(s)/PI(s), will be eligible to attend SC meetings. PIs
are encouraged to include investigators and trainees who are members of
under-represented minority groups and those from different but related disciplines
such as bioinformatics, public health, social sciences, and translational
research where appropriate. The cost of 3-4 persons to attend these
meetings, as well as the costs associated with monthly conference calls, should
be included in the proposed research budget.

Data from this FOA are expected to be handled so as to
increase the value of the significant public investment in genotyping and
analysis in the participating population studies. NHGRI intends that
descriptive study materials and data generated through genotyping efforts
supported in this FOA will be widely shared with the scientific community for
research uses through NIH-supported databases such as dbGaP. Although
NHGRI expects these materials and data to be available through a database such
as dbGaP, the NHGRI does not intend dbGaP, or any single database, to become
the exclusive source of this program’s data; other databases, public web sites,
and/or publication in the scientific literature may be suitable additional
venues for data dissemination.

Applicants for this CC FOA should indicate their willingness
to cooperate with Study Investigators supported under RFA-HG-12-010 and with NHGRI in the development and design of research and analysis methods,
procedures, policies and strategies to be applied in this program. Applicants
should also describe prior experience in working as part of a research
consortium or other collaborative activities to meet individual study and
collaborative goals.

Proof of appropriate informed consent and/or IRB approval
for serving as the CC in this collaborative program, to use previously
collected data and biospecimens for genetic research, and to share the
resulting data, should be provided at the time of application submission. Only
applications describing protection of participants’ privacy and confidentiality
will be considered.

Section II. Award Information

Funding Instrument

Cooperative Agreement

Application Types Allowed

New

The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH
appropriations, and the submission of a sufficient number of meritorious
applications.

NIH intends to fund 1 award, corresponding to a total of $800K,
for fiscal year 2013. Future year amounts will depend on annual appropriations.

Award Budget

Individual application budgets should not exceed $800,000
total costs per year and must reflect actual needs of the proposed project.

Award Project Period

The total award period requested for this FOA may not
exceed four years.

NIH grants policies as
described in the NIH
Grants Policy Statement will apply
to the applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH
Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs
requested for any one year, should address a Data Sharing Plan.

Appendix

Do not use the Appendix to circumvent page limits. Follow
all instructions for the Appendix as described in the SF424 (R&R)
Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

In order to expedite review, applicants are requested to
notify the NHGRI Referral Office by email at nakamurk@mail.nih.gov when the application has been submitted. Please include the FOA number and
title, PD/PI name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

How likely is the project to improve the assessment
and expand the understanding of ancestral differences in disease associations
with genomic variants of ancestral differences in SNP-disease associations?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Are the plans for assisting with assessment of
genotyping technologies, phenotype harmonization, providing logistical support
and fulfilling other Coordinating Center functions likely to increase the
synergy and productivity of the program? Are the plans to facilitate and
organize the sharing of consortium data in a timely manner adequate?

Innovation

Does the application challenge and seek to shift current
research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Are the proposed approaches for phenotype
harmonization and for collecting, collating, and disseminating information from
investigative groups in one or more centralized datasets adequate? Are
the proposed plans to share data in a timely manner likely to provide maximal
scientific value for expanding understanding of ancestral differences in
SNP-disease associations?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Have the investigators documented their experience
with working with large-scale population-based data, including familiarity with
phenotype harmonization and statistical analysis in a highly-effective
collaborative relationship? Does the PD(s)/PI(s) investigative team bring
complementary and integrated expertise to the project, including biostatistics,
epidemiology, and genetics/genomics, as applicable? Are the investigators
willing to collaborate with each other, the NIH, and related existing efforts,
including other NIH-funded and non-NIH funded programs in genome-wide studies,
consistent with meeting the aims of this program? Is the bioinformatics
infrastructure sufficient to accomplish the goals of the project?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety,
biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NHGRI, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of
review by the National Advisory Council on Human Genome Research. The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

Complementarity to and synergy with other funded projects.

Additional criteria for award will include:

Quality and ease of use of the proposed approaches for data synthesis
and dissemination.

Willingness of PD/PI and co-investigators to collaborate with the
NIH and with other investigative groups participating in the program.

For existing Phase I sites, ongoing productivity and
collaboration in PAGE.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD(s)/PI(s) will be able to access his or her Summary Statement (written
critique) via the eRA Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

Synthesizing genotype and phenotype datasets from each
investigative group into one or more centralized datasets for consortium-wide
analysis and dissemination to the broader scientific community, to include:

Phenotype
harmonization efforts

Data cleaning and
quality control

Providing integrative and supporting functions for the entire
program.

Providing assistance as needed to investigative groups for data
analysis (especially multi-study analyses as needed), to NCBI for receiving and
disseminating data, and to the NHGRI Program Office for program management.

Sharing results according to the data sharing policy developed
for and by this program.

Ensuring that the centralized dataset(s) and analytic tools
produced by the CC are made publicly available.

Fully disclosing all data cleaning and phenotype harmonization
methods, algorithms, and software source code, to the other members of the
program for purposes of scientific evaluation and application, as well as
dissemination and implementation throughout the scientific community.

Monitoring implementation by investigative groups of SC
recommendations for identifying optimal genomic assays or technologies and for
assaying, analyzing, and disseminating the resulting data in a timely manner.

Proposing and coming to consensus on formats for information to
be provided by investigative groups on their participating studies, and then
collating and providing this information through databases such as dbGaP
including:

Characteristics of
the participating studies, including numbers of participants and their
demographics, data collected, consent provisions, opportunities for collaboration,
etc.

Analyses of genetic
variants in relation to multiple phenotypes available within PAGE

Dates of completion
of genotyping, of completion of analyses, and of deposition for
dissemination.

Adhering to policies regarding data access, publication, and
intellectual property established by NIH and the SC for this program.

Cooperating with other awardees in the development and design of
innovative research methods, protocols, tools, and strategies.

Abiding by common definitions, protocols, procedures, etc. as
chosen by majority vote of the SC.

Accepting and complying with study policies established by NIH,
and with additional non-conflicting policies approved by the SC.

Reporting to the SC in depth, on a periodic basis, of key
findings and lessons learned.

Cooperating with other awardees in the publication and
dissemination of Program results and the eventual release to the scientific
community of methods, tools, results, and other resources.

Not disclosing confidential information obtained from other
members of the program.

Notifying the Project Scientist of all major interactions with
another member of the SC.

Submitting periodic progress reports in a standard format, as
agreed upon by the SC and ESP.

Attending and participating in SC meetings and accepting and
implementing the guidelines and procedures of the ESP and NIH, as appropriate.

Agreeing to accept close coordination, cooperation, and
management of the project as described below.

Awardees will retain custody of and
have primary rights to the data and software developed under these awards,
subject to Government rights of access consistent with current DHHS, PHS, and
NIH policies.

NIH
staff have substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below:

The Project Scientist is a scientist of the NHGRI staff who
will have substantial scientific and programmatic involvement during the
conduct of this activity through technical assistance, advice, and
coordination. However, the role of NIH staff will be to facilitate and
not to direct the activities. It is anticipated that decisions in all
activities will be reached by consensus of the program and that NIH staff will
be given the opportunity to offer input to this process. The Project
Scientist will participate as a member of the SC and will have one vote.
The Project Scientist will have the following substantial involvement:

Participating with the other SC members in the group process of
setting research priorities, deciding optimal research approaches and protocol
designs, and contributing to the adjustment of research protocols or approaches
as warranted. The Project Scientist will assist and facilitate the group
process and not direct it.

Serving as a liaison, helping to coordinate activities among and
for the awardees, including acting as a liaison to the NIH, and as an
information resource for the awardees about genome research activities.
The Project Scientist will also coordinate the efforts of the program with
other groups conducting similar studies.

Attending all SC meetings as a voting member and assisting in
developing operating guidelines, quality control procedures, and consistent
policies for dealing with situations that require coordinated action. The
Project Scientist will work with the CC as needed to manage the logistic
aspects of the program.

Reporting periodically on the progress of the program to the
Director, NHGRI and to the National Advisory Council for Human Genome Research.

Retaining the option to recommend the withholding or reduction of
support from any project that fails to achieve its goals or comply with the
Terms and Conditions of award.

Providing relevant expertise and overall knowledge of
NIH-sponsored research to facilitate the selection of scientists not affiliated
with the awardee institutions to serve on the ESP.

Serving as a liaison between the SC and the ESP, attending ESP
meetings in a non-voting liaison member role, and arranging for timely
preparation and distribution of meeting minutes.

Serving on subcommittees of the SC and the ESP, as appropriate.

Assisting awardees in the development, if needed, of policies for
dealing with situations that require coordinated action.

Providing advice in the management and technical performance of
the award.

Assisting in promoting the availability of the data and related
resources developed in the course of this program to the scientific community
at large.

Participating in data analyses, interpretations, and, where
warranted, co-authorship of the publication of results of studies conducted
through the program.

If re-consent is necessary, plans for re-consent, including
consent forms, must be reviewed by the NHGRI Program Official prior to
implementation.

Additionally, an agency program official or IC program director
will be responsible for the normal scientific and programmatic stewardship of
the award and will be named in the award notice.

Other NHGRI staff may assist the awardees, as designated by the
Program Official.

Collaborative
Responsibilities

Close interaction among the participating investigators will
be required, as well as significant involvement from the NIH, to develop
appropriate strategies and tools to design, perform, and analyze studies of
ancestral differences in genomic variation associated with human diseases. The
awardees and the Project Scientist will meet as the program SC three times per
year and monthly on conference calls as needed to share information on data
resources, methodologies, analytical tools, as well as data and preliminary
results. Key co-investigators and pre- and postdoctoral trainees, especially
those who are members of under-represented minority groups or those from different
but related disciplines, in addition to the PD(s)/PI(s), are eligible to attend
these meetings.

The SC will serve as the main scientific body of the
program. The SC will be responsible for coordinating the activities being
conducted by the program. The SC membership will include one NHGRI Project
Scientist and the PD/PI from each awarded cooperative agreement. The SC may
add additional members, and other government staff may attend the SC meetings
as desired. It is anticipated that additional coordination mechanisms may be
set up with other U.S. and international groups that may collaborate with the
program.

Each full member (PD/PI or NHGRI Project Scientist) will
have one vote. Awardee members of the SC will be required to accept and implement
policies approved by the SC.

As described above, PAGE II will convene working groups to
plan and implement cross-study activities. The PAGE II SC will have the
overall responsibility of assessing and prioritizing the progress of the
various working groups. Awardees agree to work collaboratively to:

As needed, assess the need for and implement plans to develop
customized genotyping arrays to include genomic variation representative of
multiple ancestral groups,.

Share experience and expertise across participating studies and
develop best practices for prioritizing genomic regions and study participants
and on collecting, formatting, depositing, and documenting descriptive and
association data for databases such as dbGaP, for widespread dissemination and
to maximize the value of the consortium.

Evaluate existing phenotypic and exposure data in participating
studies for completeness, biases, standardization, and reproducibility; and on
documentation, compatibility with dbGaP or other databases, and relevance to
investigation of ancestral differences in genomic variant-disease associations.

Interact with other relevant NHGRI and NIH activities, as needed,
to promote synergy and consistency among similar projects.

External
Scientific Panel

An External Scientific Panel (ESP) will continue to evaluate
the progress of the program. The ESP will provide recommendations to the
National Advisory Council for Human Genome Research about the progress and
scientific direction of all components of the program.

The ESP is currently composed of five senior scientists with
relevant expertise, although in PAGE II the ESP may be augmented permanently or
on an ad hoc basis as needed. The ESP will continue to meet at least twice a
year; some meetings may be conducted by telephone conference. Occasionally, the
ESP may be asked to advise PAGE Investigators and the NHGRI on timely issues
during the interim period between meetings. At least once a year, there will
be a joint meeting with the SC to allow the members of the both the ESP and the
SC to interact directly. Twice a year the ESP will make recommendations
regarding progress of the program to the National Advisory Council for Human
Genome Research about changes, if any, which may be necessary in the program.

Dispute
Resolution:

Any disagreements that may arise in scientific or programmatic
matters (within the scope of the award) between award recipients and the NIH
may be brought to Dispute Resolution. A Dispute Resolution Panel composed of
three members will be convened. It will have three members: a designee of the SC
chosen without NIH staff voting, one NIH designee, and a third designee with
expertise in the relevant area who is chosen by the other two; in the case of
individual disagreement, the first member may be chosen by the individual
awardee. This special dispute resolution procedure does not alter the awardee's
right to appeal an adverse action that is otherwise appealable in accordance
with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part
16.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH
Grants Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.